An important liver functional paramter which has received essentially no attention and, yet, may result in serious consequences in the event of an age-related decline, is the hepatobiliary system. The few reports describing age-dependent declines in the function of this system are inconclusive and often present conflicting evidence. A decrease in hepatobilhary function affects not only the enterohepatic circulation of bile salts, but may also interfere with the elimination of certain drugs or the secretion of immunoglobulin A (IgA) via the biliary tract. Interestingly, the rate of overall drug disposition declines significantly as a function of age. The incidence of gastrointestinal disease, including cancer, and the concentration of circulating IgA increase with age, suggesting that less IgA reaches the gastrointestinal tract in the elderly. The proposed research is intended to evaluate the efficacy of the hepatobiliary system in young, mature and senescent animals and humans. We anticipate identifying the mechanisms for and/or the hepatocellular sites of any ange-related changes and their effect(s) on the hepatic secretion of IgA and excretion of a representative drug, ouabain. A number of methods, both structural and functional, including electron microscopy, stereology, quantitative autoradiography, radioactive tracer techniques and enzyme analyses, will be used in these studies. A recently developed technique for maintaining liver tissue in organ culture will be used to examine the hepatic uptake and transcellular transport of IgA as a function of donor age in humans. In addition, these proposed studies require the development of a method for separating centrolobular and periportal rat hepatocytes in order to examine two hypotheses: (1) that centrolobular hepatocytes represent an "older" population of cells than the respective periportal cells and (2) that the suspected lobular gradients in hepatocellular function may be subject to age-related changes which are manifested in a reduced hepatic responsiveness, e.g. reduced hepatobiliary function.